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Comparison of relative telomere length measured in aortic tissue and leukocytes in patients after heart transplantation
Abstracts / Atherosclerosis 263 (2017) e111ee282
Dana Dlouha1, Vlastimil Vancura2, 3, Jevgenija Vymetalova3, Jaroslav Alois Hubacek1, Vera Lanska1, Ivan Malek3. 1 Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2 University Hospital and Faculty of Medicine Pilsen, Charles University Prague, Prague, Czech Republic; 3 Cardiology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Aim: In humans, leukocyte telomere length (LTL) reduces with age and is reported to be inversely associated with ageing-related diseases. If LTL could reflect survival length of patients after heart allograft transplantation was a hypothesis of our study. Methods: We measured LTL in leukocyte DNA using a quantitative PCRbased method from 127 blood samples of heart recipients (107 males, 20 females, age 44.1 ± 10.5), followed for up to 30 years. Results: Patients with coronary artery disease survived for a shorter time and also had shorter LTL (both P < 0.05 after adjustment for age and sex) than subjects with dilated cardiomyopathy. Patients with non-cardiac causes of death had shorter LTL than patients with cardiac causes (P < 0.05 after adjustment for age). An inverse correlation between LTL and age (P < 0.03) was observed in patients with non-cardiac causes of death only. LTL was not associated with general survival time in patients after heart transplantation. Conclusions: LTL was not associated with general survival time in patients after heart transplantation. Shorter LTL was a marker of non-cardiac causes of death. Different LTLs and survival times were determined in association with etiology of heart failure (HF). Funding sources: Supported by project MH-CR, IN 00230001, IKEM. All rights reserved.
PO547. COMPARISON OF RELATIVE TELOMERE LENGTH MEASURED IN AORTIC TISSUE AND LEUKOCYTES IN PATIENTS AFTER HEART TRANSPLANTATION Dana Dlouha1, Jevgenija Vymetalova2, Ivan Malek2, Jaroslav Alois Hubacek1. 1 Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2 Cardiology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Aim: Telomeres are repetitive non-coding DNA sequences on the ends of eukaryotic chromosomes. Relative leukocyte telomere length (LrTL) is considered to reflect biological aging and fitness. Therefore, we examined whether LrTL would reflect rTL in aortic tissue (ArTL) and whether it could be used as a marker of biological heart age. Methods: We analyzed telomere length in aortic and leukocyte samples from 73 heart recipients (63 males, 10 females; age 52.2 ± 11.7 years). Relative telomere length was measured using a quantitative PCR-based method. Results: Neither LrTL nor ArTL correlated significantly with the age of heart recipients. Mean ArTL was slightly shorter than LrTL (P ¼ 0.06) and there was a slight but significant inverse correlation between LrTL and ArTL (P ¼ 0.019). Conclusions: The age of patients with severe heart failure was not associated with leukocyte or aortic telomere length. An inverse correlation between LrTL and ArTL suggests that LrTL is unlikely to be an important predictor of biological aging in these patients. Funding sources: Supported by project MH-CR, IN 00230001, IKEM. All rights reserved.
PO548. INTERCONNECTION BETWEEN CAVI-1 AND GENETIC MARKERS IN PATIENTS WITH HIGH CARDIOVASCULAR RISK Natalya Koziolova, Anna Chernyavina. Perm State Medical University n.a. ac. E.A.Wagner, Perm, Russia Aim: to evaluate interconnection between CAVI-1 and genetic markers in patients with high cardiovascular risk.
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Methods: 187 working-age subjects with high cardiovascular risk were examined of average age 48,74±7,41 yrs. Subjects were divided into 2 groups depending on CAVI-1. The first group consisted of 115 patients with CAVI-1 9.0. All patients underwent volume sphygmopletismography by VaSera VS-1000 (Japan), and genetic genotypes of markers AGT Thr174Met, GNB3 C825T, MTHFR C677T, MTRR Ile22Met, ApoE Cys130Arg. Results: patients in the groups did not differ in sex, age, risk factors, comorbidities, concomitant medications, BP level, lipid spectrum. In the 1st group gene heterozygous polymorphism of AGT, GB3 and MTHFR presented reliably frequently, than in 2nd group (p¼0,041, p¼0,032 and p¼0,023, respectively). Patients with CAVI-1>9.0 had more frequent homozygous and heterozygous polymorphism of MTRR (p¼0,028). Frequency of ApoE gene polymorphism did not differ between the groups. Correlation analysis showed moderate degree of dependency between CAVI-1 and polymorphism of following genes: AGT (r¼0,34; p¼0,025), GNB3 (r¼0,45; p¼0,031), MTHFR (r¼0,37; p¼0,004), MTRR (r¼0,41; p¼0,027). Correlation between CAVI-1 and ApoE polymorphism was not revealed. Conclusions: CAVI-1 increase in working-age subjects with high cardiovascular risk is associated with polymorphism of genes AGT, GB3 and MTHFR in heterozygous, and gene MTRR in heterozygous and homozygous.
PO549. MOLECULAR GENETICS OF FAMILIAL HYPERCHOLESTEROLEMIA IN ISRAEL e REVISITED Durst Ronen1, Uche Ken Ibe3, Shpitzen Shoshi2, Schurr Daniel2, Futema Marta3, Whittal Ros3, Szalat Auryan2, Knobler Hilla5, Gavish Dov6, Henkin Yaakov7, Ellis Avishay8, Rubinstein Ardon9, Harats Dror10, Bitzur Rafael10, Hershkovit Bruno1, Humphrie Steve E3, Leitersdorf Eran2, Vardilla Meiner4. 1 Department of Cardiology, Hadassah Hebrew University Medical Center, Jeusalem, Israel; 2 Center for Research Prevention and Treatment of atherosclerosis, Department of Medicine, Jerusalem, Israel; 3 Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, Univ, London, United Kingdom; 4 Department of Genetics and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel; 5 Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot, Israel; 6 Department of Medicine, Wolfson Medical Center, Holon, Israel; 7 Department of Cardiology, Soroka University Medical Center, Beer Sheva, Israel; 8 Internal Medicine, Rabin Medical Center, Petah Tikva, Israel; 9 Department of Metabolic Clinic, Tel Aviv Medical Center, Tel Aviv, Israel; 10 Bert W. Strassburger Lipid Center, the Chaim Sheba Medical Center, Ramat Gan, Israel Aim: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and Proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel. Methods: New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes were done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping. Results: Mean cholesterol was 7.48±1.89mmol/L and the LDL-C was 5.99±1.89mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), 16 in LDLR, none in PCSK9 and one, p.(R3527Q) in the APOB gene. Two novel LDLR mutations, p.(E140A) and c.-191C>A were found. The c.2479G>A p.(V827I) in exon 17 of the LDLR was found in 8 patients (33.3% of mutations) modestly elevating LDL-C but also in a compound heterozygous patient with a clinical homozygous FH phenotype, suggesting “mild” FH- variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian (p¼0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy. Conclusions: The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous
Dana Dlouha1, Vlastimil Vancura2, 3, Jevgenija Vymetalova3, Jaroslav Alois Hubacek1, Vera Lanska1, Ivan Malek3. 1 Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2 University Hospital and Faculty of Medicine Pilsen, Charles University Prague, Prague, Czech Republic; 3 Cardiology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Aim: In humans, leukocyte telomere length (LTL) reduces with age and is reported to be inversely associated with ageing-related diseases. If LTL could reflect survival length of patients after heart allograft transplantation was a hypothesis of our study. Methods: We measured LTL in leukocyte DNA using a quantitative PCRbased method from 127 blood samples of heart recipients (107 males, 20 females, age 44.1 ± 10.5), followed for up to 30 years. Results: Patients with coronary artery disease survived for a shorter time and also had shorter LTL (both P < 0.05 after adjustment for age and sex) than subjects with dilated cardiomyopathy. Patients with non-cardiac causes of death had shorter LTL than patients with cardiac causes (P < 0.05 after adjustment for age). An inverse correlation between LTL and age (P < 0.03) was observed in patients with non-cardiac causes of death only. LTL was not associated with general survival time in patients after heart transplantation. Conclusions: LTL was not associated with general survival time in patients after heart transplantation. Shorter LTL was a marker of non-cardiac causes of death. Different LTLs and survival times were determined in association with etiology of heart failure (HF). Funding sources: Supported by project MH-CR, IN 00230001, IKEM. All rights reserved.
PO547. COMPARISON OF RELATIVE TELOMERE LENGTH MEASURED IN AORTIC TISSUE AND LEUKOCYTES IN PATIENTS AFTER HEART TRANSPLANTATION Dana Dlouha1, Jevgenija Vymetalova2, Ivan Malek2, Jaroslav Alois Hubacek1. 1 Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic; 2 Cardiology Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic Aim: Telomeres are repetitive non-coding DNA sequences on the ends of eukaryotic chromosomes. Relative leukocyte telomere length (LrTL) is considered to reflect biological aging and fitness. Therefore, we examined whether LrTL would reflect rTL in aortic tissue (ArTL) and whether it could be used as a marker of biological heart age. Methods: We analyzed telomere length in aortic and leukocyte samples from 73 heart recipients (63 males, 10 females; age 52.2 ± 11.7 years). Relative telomere length was measured using a quantitative PCR-based method. Results: Neither LrTL nor ArTL correlated significantly with the age of heart recipients. Mean ArTL was slightly shorter than LrTL (P ¼ 0.06) and there was a slight but significant inverse correlation between LrTL and ArTL (P ¼ 0.019). Conclusions: The age of patients with severe heart failure was not associated with leukocyte or aortic telomere length. An inverse correlation between LrTL and ArTL suggests that LrTL is unlikely to be an important predictor of biological aging in these patients. Funding sources: Supported by project MH-CR, IN 00230001, IKEM. All rights reserved.
PO548. INTERCONNECTION BETWEEN CAVI-1 AND GENETIC MARKERS IN PATIENTS WITH HIGH CARDIOVASCULAR RISK Natalya Koziolova, Anna Chernyavina. Perm State Medical University n.a. ac. E.A.Wagner, Perm, Russia Aim: to evaluate interconnection between CAVI-1 and genetic markers in patients with high cardiovascular risk.
e279
Methods: 187 working-age subjects with high cardiovascular risk were examined of average age 48,74±7,41 yrs. Subjects were divided into 2 groups depending on CAVI-1. The first group consisted of 115 patients with CAVI-1 9.0. All patients underwent volume sphygmopletismography by VaSera VS-1000 (Japan), and genetic genotypes of markers AGT Thr174Met, GNB3 C825T, MTHFR C677T, MTRR Ile22Met, ApoE Cys130Arg. Results: patients in the groups did not differ in sex, age, risk factors, comorbidities, concomitant medications, BP level, lipid spectrum. In the 1st group gene heterozygous polymorphism of AGT, GB3 and MTHFR presented reliably frequently, than in 2nd group (p¼0,041, p¼0,032 and p¼0,023, respectively). Patients with CAVI-1>9.0 had more frequent homozygous and heterozygous polymorphism of MTRR (p¼0,028). Frequency of ApoE gene polymorphism did not differ between the groups. Correlation analysis showed moderate degree of dependency between CAVI-1 and polymorphism of following genes: AGT (r¼0,34; p¼0,025), GNB3 (r¼0,45; p¼0,031), MTHFR (r¼0,37; p¼0,004), MTRR (r¼0,41; p¼0,027). Correlation between CAVI-1 and ApoE polymorphism was not revealed. Conclusions: CAVI-1 increase in working-age subjects with high cardiovascular risk is associated with polymorphism of genes AGT, GB3 and MTHFR in heterozygous, and gene MTRR in heterozygous and homozygous.
PO549. MOLECULAR GENETICS OF FAMILIAL HYPERCHOLESTEROLEMIA IN ISRAEL e REVISITED Durst Ronen1, Uche Ken Ibe3, Shpitzen Shoshi2, Schurr Daniel2, Futema Marta3, Whittal Ros3, Szalat Auryan2, Knobler Hilla5, Gavish Dov6, Henkin Yaakov7, Ellis Avishay8, Rubinstein Ardon9, Harats Dror10, Bitzur Rafael10, Hershkovit Bruno1, Humphrie Steve E3, Leitersdorf Eran2, Vardilla Meiner4. 1 Department of Cardiology, Hadassah Hebrew University Medical Center, Jeusalem, Israel; 2 Center for Research Prevention and Treatment of atherosclerosis, Department of Medicine, Jerusalem, Israel; 3 Centre for Cardiovascular Genetics, British Heart Foundation Laboratories, Institute of Cardiovascular Sciences, Univ, London, United Kingdom; 4 Department of Genetics and Metabolic Diseases, Hadassah Hebrew University Medical Center, Jerusalem, Israel; 5 Diabetes and Metabolic Disease Unit, Kaplan Medical Center, Rehovot, Israel; 6 Department of Medicine, Wolfson Medical Center, Holon, Israel; 7 Department of Cardiology, Soroka University Medical Center, Beer Sheva, Israel; 8 Internal Medicine, Rabin Medical Center, Petah Tikva, Israel; 9 Department of Metabolic Clinic, Tel Aviv Medical Center, Tel Aviv, Israel; 10 Bert W. Strassburger Lipid Center, the Chaim Sheba Medical Center, Ramat Gan, Israel Aim: Familial hypercholesterolemia (FH) is an autosomal dominant disease caused by mutations in the genes for LDL receptor (LDLR), apolipoprotein B (APOB) and Proprotein convertase subtilisin/kexin type9 (PCSK9). The purpose of the current investigation was to define the current spectrum of mutations causing FH in Israel. Methods: New families were collected through the MEDPED (Make Early Diagnosis Prevent Early Death) FH program. Molecular analysis of the LDLR, PCSK9 and APOB genes were done using High Resolution Melt and direct sequencing in 67 index cases. A 6-SNP LDL-C gene score calculation for polygenic hypercholesterolaemia was done using TaqMan genotyping. Results: Mean cholesterol was 7.48±1.89mmol/L and the LDL-C was 5.99±1.89mmol/L. Mutations in the LDLR and APOB gene were found in 24 cases (35.8%), 16 in LDLR, none in PCSK9 and one, p.(R3527Q) in the APOB gene. Two novel LDLR mutations, p.(E140A) and c.-191C>A were found. The c.2479G>A p.(V827I) in exon 17 of the LDLR was found in 8 patients (33.3% of mutations) modestly elevating LDL-C but also in a compound heterozygous patient with a clinical homozygous FH phenotype, suggesting “mild” FH- variant. A significantly higher 6-SNP LDL-C score was found in mutation-negative cases compared with a normal Caucasian (p¼0.03), confirming that polygenic inheritance of common LDL-C raising SNPs can produce an FH phenocopy. Conclusions: The results indicate a different spectrum of genetic causes of FH from that found previously, in concordance with the heterogeneous